Matthew J. Shepard, Mohamed A. Elzoghby, Erin N. Kiehna, Spencer C. Payne and John A. Jane Jr.
Rathke cleft cysts (RCCs) are sellar lesions that are commonly encountered in adults but infrequently diagnosed in the pediatric population. As a result, the optimal management of pediatric RCCs remains a subject of controversy. Only 2 prior surgical series have been published on pediatric RCCs and no study has compared the presentation and outcomes of surgically versus conservatively managed cases. The authors therefore performed a comparative analysis of pediatric cases of RCC in which patients were treated with surgery or managed in a conservative manner.
All cases involving pediatric patients diagnosed with an RCC at the University of Virginia between 2000 and 2016 were included in this study. Patient medical records, operative notes, and neuroimaging findings were reviewed. Patients who developed visual field deficits, radiographic evidence of chiasmal compression, or medically refractory headaches were considered candidates for surgical intervention. All patients who were selected for surgery underwent an endoscopic endonasal approach with cyst fenestration.
A total of 24 pediatric patients were diagnosed with an RCC over a 16-year period. Seven patients ultimately underwent transsphenoidal cyst fenestration, and 17 were managed conservatively. The patients’ age at diagnosis, cyst size, and pituitary function at the time of RCC diagnosis were similar in the conservatively and surgically managed cohorts. At diagnosis, 19 of 24 patients endorsed headaches that led to neuroimaging. All patients in the surgical cohort endorsed severe headaches at diagnosis compared with 71% in the conservative group. For the 7 patients treated with surgery, complete cyst evacuation was achieved in 86% of cases. Transient postoperative endocrinopathy occurred in 4 (57%) of 7 surgically treated individuals and resolved in all cases. In the conservative cohort, 1 patient developed a delayed pituitary-related endocrinopathy. Headache resolution occurred in 5 (71%) of the 7 patients who underwent surgery and 7 (58%) of the 12 who were treated without surgery. Cyst recurrence was documented in 1 individual in the surgical cohort who underwent a subtotal cyst fenestration that ultimately required re-intervention. In the conservative cohort, spontaneous cyst shrinkage occurred in 35% of patients with a median time to regression of 23.5 months.
Pediatric RCCs are benign sellar lesions that often present with headaches. While cyst fenestration mitigates headaches in most patients, the majority of conservatively managed pediatric patients with RCCs will have spontaneous headache resolution. Furthermore, spontaneous RCC regression occurs in a substantial number of individuals. Thus, in the absence of optic compression, visual field deficit, or diagnostic uncertainty, many pediatric cases of RCC can be managed conservatively.
Matthew J. Shepard and W. Jeffrey Elias
Davis G. Taylor, Thomas J. Buell, Tony R. Wang, Matthew J. Shepard, Dominic Maggio, Ching-Jen Chen, Min S. Park and Mark E. Shaffrey
Matthew J. Shepard, Alejandro Bugarini, Nancy A. Edwards, Jie Lu, Qi Zhang, Tianxia Wu, Zhengping Zhuang and Prashant Chittiboina
Von Hippel-Lindau disease (VHL) is a tumor predisposition syndrome characterized by CNS hemangioblastomas (HBs) and clear cell renal cell carcinomas (RCCs) due to hypoxia-inducible factor activation (pseudohypoxia). Because of the lack of effective medical therapies for VHL, HBs and RCCs account for significant morbidity and mortality, ultimately necessitating numerous neurological and renal surgeries. Propranolol is an FDA-approved pan-beta adrenergic antagonist with antitumor effects against infantile hemangiomas (IHs) and possibly VHL HBs. Here, the authors investigated the antitumor efficacy of propranolol against pseudohypoxia-driven VHL-HBs and VHL-RCCs.
Patient-derived VHL-associated HBs (VHL-HBs) or 786-O-VHL
−/− RCC cells were treated with clinically relevant concentrations of propranolol in vitro and assessed with viability assays, flow cytometry, quantitative real-time polymerase chain reaction, and western blotting. In vivo confirmation of propranolol antitumor activity was confirmed in athymic nude mice bearing 786-O xenograft tumors. Lastly, patients enrolled in a VHL natural history study (NCT00005902) were analyzed for incidental propranolol intake. Propranolol activity against VHL-HBs was assessed retrospectively with volumetric HB growth kinetic analysis.
Propranolol decreased HB and RCC viability in vitro with IC50 (half maximal inhibitory concentration) values of 50 µM and 200 µM, respectively. Similar to prior reports in infantile hemangiomas, propranolol induced apoptosis and paradoxically increased VEGF-A mRNA expression in patient-derived VHL-HBs and 786-O cells. While intracellular VEGF protein levels were not affected by propranolol treatment, propranolol decreased HIF expression in 786-O cells (7.6-fold reduction, p < 0.005). Propranolol attenuated tumor progression compared with control (33% volume reduction at 7 days, p < 0.005) in 786-O xenografted tumor-bearing mice. Three patients (harboring 25 growing CNS HBs) started propranolol therapy during the longitudinal VHL-HB study. HBs in these patients tended to grow slower (median growth rate 27.1 mm3/year vs 13.3 mm3/year) during propranolol treatment (p < 0.0004).
Propranolol decreases VHL-HB and VHL-related RCC viability in vitro likely by modulation of VEGF expression and by inducing apoptosis. Propranolol abrogates 786-O xenograft tumor progression in vivo, and retrospective clinical data suggest that propranolol curtails HB growth. These results suggest that propranolol may play a role in the treatment of VHL-related tumors.
Matthew J. Shepard, Zhiyuan Xu, Joseph Donahue, Thomas J. Eluvathingal Muttikkal, Diogo Cordeiro, Leslie Hansen, Nasser Mohammed, Ryan D. Gentzler, James Larner, Camilo E. Fadul and Jason P. Sheehan
Immune checkpoint inhibitors (ICIs) improve survival in patients with advanced non–small cell lung cancer (NSCLC). Clinical trials examining the efficacy of ICIs in patients with NSCLC excluded patients with untreated brain metastases (BMs). As stereotactic radiosurgery (SRS) is commonly employed for NSCLC-BMs, the authors sought to define the safety and radiological and clinical outcomes for patients with NSCLC-BMs treated with concurrent ICI and SRS.
A retrospective matched cohort study was performed on patients who had undergone SRS for one or more NSCLC-derived BMs. Two matched cohorts were identified: one that received ICI before or after SRS within a 3-month period (concurrent ICI) and one that did not (ICI naive). Locoregional tumor control, peritumoral edema, and central nervous system (CNS) adverse events were compared between the two cohorts.
Seventeen patients (45 BMs) and 34 patients (92 BMs) composed the concurrent-ICI and ICI-naive cohorts, respectively. There was no statistically significant difference in overall survival (HR 0.99, 95% CI 0.39–2.52, p = 0.99) or CNS progression-free survival (HR 2.18, 95% CI 0.72–6.62, p = 0.11) between the two groups. Similarly, the 12-month local tumor control rate was 84.9% for tumors in the concurrent-ICI cohort versus 76.3% for tumors in the ICI-naive cohort (p = 0.94). Further analysis did reveal that patients receiving concurrent ICI had increased rates of CNS complete response for BMs treated with SRS (8/16 [50%] vs 5/32 [15.6%], p = 0.012) per the Response Assessment in Neuro-Oncology (RANO) criteria. There was also a shorter median time to BM regression in the concurrent-ICI cohort (2.5 vs 3.1 months, p < 0.0001). There was no increased rate of radiation necrosis or intratumoral hemorrhage in the patients receiving concurrent ICI (5.9% vs 2.9% in ICI-naive cohort, p = 0.99). There was no significant difference in the rate of peritumoral edema progression between the two groups (concurrent ICI: 11.1%, ICI naive: 21.7%, p = 0.162).
The concurrent use of ICI and SRS to treat NSCLC-BM was well tolerated while providing more rapid BM regression. Concurrent ICI did not increase peritumoral edema or rates of radiation necrosis. Further studies are needed to evaluate whether combined ICI and SRS improves progression-free survival and overall survival for patients with metastatic NSCLC.